After leading the Tampa Bay Rays by nine games in the AL wild card race on September 3—when their odds of reaching the postseason peaked at 99.6%—the Red Sox lost 18 of their final 24 games.[6] On the last day of the season, September 28, a ninth inning Red Sox blown save loss against the Baltimore Orioles,[7] coupled with an extra inning come from behind victory by the Rays over the Yankees,[8] made the Rays the AL wild card winners, eliminating the Red Sox from postseason contention. It is regarded as one of the biggest collapses and franchise fails in MLB history.

Fans gathered at Fenway Park on February 8, 2011 in order to kick off the Red Sox preseason by celebrating Truck Day. The first full team workout of the preseason took place on February 19.[9] Playing other teams in the Grapefruit League the Red Sox finished with 14 wins and 19 losses.[10]

The Red Sox made a statement in the offseason, letting everyone know that after missing the playoffs last year, they are striving to win the World Series this year, but instead imploded in dramatic fashion in September and failed to make the playoffs. During the offseason the Red Sox traded for first baseman Adrian Gonzalez,[11] and they followed that move up by signing star outfielder Carl Crawford.[12]

On May 15, John Lackey and Daisuke Matsuzaka were placed on the disabled list. On June 10, Matsuzaka underwent season-ending Tommy John surgery. Clay Buchholz was afflicted with what would be diagnosed as a stress fracture in his back and was also put on the disabled list on June 17, where he would remain for the rest of the season. Other pitchers including Rich Hill and Bobby Jenks spent significant time on the disabled list. The Red Sox obtained Érik Bédard from the Seattle Mariners seconds before the trading deadline, after Kyle Weiland (who was highlighted by his ejection on his MLB debut) proved ineffective. Starting pitchers John Lackey and ace Jon Lester were ineffective down the stretch, as the Red Sox crashed down to a 7-20 finish, blowing a 9-game wild card lead that they held entering September. Josh Beckett missed a start early in the month after spraining his ankle in a previous start, and was ineffective in most of his September starts after that point.

The Red Sox became the first team in the history of Major League Baseball to have a nine-game lead in September and fail to make the playoffs that season, thanks to their 7—20 record in the final month of the regular season.[17] In the days following this historic collapse, the front office and manager Terry Francona decided to part ways, and not exercise either of the additional year options on Francona's contract.

After the regular season ended, General Manager Theo Epstein entered talks with the Chicago Cubs to interview for the National League club's vacant General Manager position. The Cubs offered Epstein the position of President of Baseball Operations, and he accepted. After five months of negotiations, the Red Sox and Cubs agreed to the compensation the Red Sox would receive for Epstein. The Cubs acquired minor-league first baseman Jair Bogaerts (twin brother of Xander Bogaerts) from the Red Sox, and the Red Sox received pitchers Chris Carpenter and Aaron Kurcz.

Soon after the season ended, stories broke in the local media about several of Boston's starting pitchers, including Jon Lester, Josh Beckett, and John Lackey, had been playing video games, eating fried chicken, and drinking beer in the clubhouse and dugout during games when they were not pitching. Jon Lester was the first to speak publicly about the allegations, and admitted to eating and drinking in the clubhouse during games, though infrequently, but denied that these actions ever took place in the dugout.[18]